A Single-Arm, Phase II Study of Apatinib in Refractory Metastatic Colorectal Cancer
A Single-Arm, Phase II Study of Apatinib in Refractory Metastatic Colorectal Cancer
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DOI：
10.1634/theoncologist.2019-0164
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发表时间：
2019-07-01
期刊：
影响因子：
5.8
通讯作者：
Gu, Yanhong
中科院分区：
文献类型：
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作者：
Chen, Xiaofeng;Qiu, Tianzhu;Gu, Yanhong
背景阿帕替尼是一种口服血管内皮生长因子（VEGF）受体-2抑制剂，在中国已被批准作为转移性胃癌的三线治疗药物。本研究的目的是评价阿帕替尼治疗二线或二线以上化疗失败的难治性转移性结直肠癌患者的疗效和安全性。方法在这项开放标签、单组、II期研究中，具有结肠或直肠腺癌组织学记录的患者如果既往接受过至少两种标准治疗方案（包括氟嘧啶、奥沙利铂和伊立替康），则符合条件。这些患者接受阿帕替尼治疗，每日剂量为500 mg，p.o.，在第三行或更高的设置。动态进行捕获测序，以鉴定循环肿瘤DNA（ctDNA）中的体细胞变体，其中包含1，021个癌症相关基因。主要终点为无进展生存期（PFS），根据实体瘤疗效评价标准（RECIST）第1.1版确定肿瘤缓解。按照预定义应用中期分析。结果2016年6月1日至2017年12月31日，共入组26例患者。整个组的中位PFS为3.9个月（95%置信区间[CI]：2.1-5.9）。中位总生存期（OS）为7.9个月（95% CI：4.6-10.1+）。体能状态（PS）0-1的患者的PFS长于PS 2的患者（4.17个月vs. 1.93个月，p = 0.0014）。无肝转移患者的PFS也长于有肝转移患者（5.87个月vs. 3.33个月，p = 0.0274）。阿帕替尼的常见副作用为高血压、手足综合征、蛋白尿和腹泻。3-4级高血压、手足综合征、蛋白尿和腹泻的发生率分别为76.92%、11.54%、73.08%和23.08%。所有患者均因不良反应而减少剂量。捕获测序结果显示APC、TP 53和KRAS是最常见的突变基因。10例患者在放射学评估前ctDNA丰度增加。结论阿帕替尼单药治疗难治性结直肠癌有较好的疗效，尤其是PS 0-1或无肝转移的患者。ctDNA丰度可能是连续监测肿瘤负荷的预测因子。
Background. Apatinib, an oral vascular endothelial growth factor (VEGF) receptor-2 inhibitor, has been approved as third-line treatment for metastatic gastric cancer in China. The aim of this study was to evaluate the efficacy and safety of apatinib, in the treatment of patients with refractory metastatic colorectal cancer after failure of two or more lines of chemotherapy. Methods In this open-label, single-arm, phase II study, patients with histological documentation of adenocarcinoma of the colon or rectum were eligible if they had received at least two prior regimens of standard therapies including fluoropyrimidine, oxaliplatin, and irinotecan. These patients were treated with apatinib in a daily dose of 500 mg, p.o., in the third-line or higher setting. Capture sequencing was dynamically performed to identify somatic variants in circulating tumor DNA (ctDNA) with a panel of 1,021 cancer-related genes. The primary endpoint was progression-free survival (PFS) and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Interim analysis was applied as predefined. Results From June 1, 2016 to December 31, 2017, 26 patients were enrolled. The median PFS of the whole group was 3.9 months (95% confidence interval [CI]: 2.1-5.9). The median overall survival (OS) was 7.9 months (95% CI: 4.6-10.1+). Patients with performance status (PS) 0-1 had longer PFS than those with PS 2 (4.17 months vs. 1.93 months, p = .0014). Patients without liver metastasis also had longer PFS than those who had live metastasis (5.87 months vs. 3.33 months, p = .0274). The common side effects of apatinib were hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence of grade 3-4 hypertension, hand-foot syndrome, proteinuria, and diarrhea was 76.92%, 11.54%, 73.08%, and 23.08%, respectively. All of the patients received dose reduction because of adverse effect. Results of capture sequencing showed APC, TP53, and KRAS were most frequently mutant genes. ctDNA abundance increased before the radiographic assessment in ten patients. Conclusion Apatinib monotherapy showed promising efficiency for patients with refractory colorectal cancer, especially in patients with PS 0-1 or no liver metastasis. ctDNA abundance may be a predictor in serial monitoring of tumor load.